It seems like a week doesn’t go by without more yet more research coming to light which paints the cholesterol-reducing drugs known as ‘statins’ as wonder drugs. The latest example of such research was published earlier this month in the Annals of Internal Medicine [1].
The study was an analysis of individuals aged 65 or more who were treated with low (10 mg) or high (80 mg) of the statin atorvastatin (Lipitor) made by the drug company Pfizer. All of the individuals in the study were known to have pre-existing heart disease, which means they are generally regarded as ‘high-risk’ for events such as heart attacks and strokes. These elderly, at-risk individuals are just the sort of people you would expect to benefit most from some sort of intervention.
The ‘highlight’ of this study is that those individuals taking 80 mg of the drug compared to those taking the lower dose enjoyed a 19 per cent reduced risk of a ‘major cardiovascular event’ (e.g. heart attack or stroke) – and this difference was statistically significant. The abstract (summary) of the study goes on to tell us that: Among the components of the composite outcome, the mortality rates from CHD, nonfatal non”procedure-related myocardial infarction, and fatal or nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were all lower in older patients who received high-dose atorvastatin, although the difference was not statistically significant for each individual component. The improved clinical outcome in patients 65 years of age or older was not associated with persistent elevations in creatine kinase levels. (creatinine kinase levels go up in certain conditions including muscle breakdown and heart attack).
Looking goooood, no?
Well, first of all, let’s have a look at all those outcomes other than major cardiovascular events i.e. mortality rates from CHD, nonfatal non”procedure-related myocardial infarction, and fatal or nonfatal stroke. NONE of these outcomes were lower in the 80 mg group compared to the 10 mg group from a statistical perspective.
Bearing this in mind, doesn’t the wording in the abstract seem a little odd, or is it me?
Here are the words again: Among the components of the composite outcome, the mortality rates from CHD, nonfatal non”procedure-related myocardial infarction, and fatal or nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin) were all lower in older patients who received high-dose atorvastatin, although the difference was not statistically significant for each individual component. Actually, the truth is the difference was not statistically significant for ANY component.
Now let’s look at the hazards associated with the treatment. We are reassured in the abstract that The improved clinical outcome in patients 65 years of age or older was not associated with persistent elevations in creatine kinase levels. Closer analysis of this study reveals that the authors adjudged raised levels of creatinine kinase to be more than 10 TIMES the upper limit of normal.
And the abstract fails to draw out attention to the analysis of liver function. Deranged liver function (as defined as a level of one of two liver enzymes at more than 3 times the upper limit of normal) was found in 1 person on the lower dose of atorvastatin, compared to 24 on the higher dose.
Also, withdrawal from the study due to treatment-related side effects was twice as likely in the higher dose group (4.4. v 2.2 percent). Funny how none of this came out in the abstract. Though we can all relax in the knowledge that creatinine kinase levels were not persistently elevated to more than 10 times their normal upper limit in the higher dose group.
Overall, it would seem that the abstract puts a very shiny gloss on what, to my mind, amounts to very unimpressive results indeed. And bear in mind, this was in a group of individuals (elderly, with pre-existing heart disease) that you would expect to be ripe for benefit.
And the potential reason for this. Well, I suppose it will come as no surprise to you that the study was funded by Pfizer. We are reassured, however, that the researchers were not influenced by the trial sponsor. Here’s what it says in the paper under: ‘Role of the Funding Source’
The TNT study was funded by Pfizer. The steering committee developed the protocol in collaboration with the funding source and was responsible for the final version. ICON Clinical Research, North Wales, Pennsylvania, managed all data. ICON and Pfizer provided site monitoring throughout the study. The data were analyzed by the funding source according to the statistical analysis plan approved by the steering committee. The steering committee had unrestricted, request-based access to the study data, which were retained by the funding source, and developed the article independently without constraints from the sponsor.
So, now we know that Pfizer had a hand in designing the study, held the data and even performed the statistical analysis. Oh, but at least the steering committee could get the data if they wanted.
And now let’s look in a little more depth at that ‘steering committee’. Here’s its members’ declared ‘potential financial conflicts of interest’:
Consultancies: N.K. Wenger (Eli Lilly Inc., SmithKline Beecham, DuPont Pharma, Pfizer Inc., Merck & Co. Inc., Bristol-Myers Squibb, Aventis, Sanofi-Aventis, Schering-Plough, GlaxoSmithKline, AstraZeneca, Abbott), S.J. Lewis (Pfizer Inc., Merck & Co. Inc., Bristol-Myers Squibb, AstraZeneca), D.M. Herrington (Merck & Co. Inc.), V. Bittner (Reliant Pharmaceuticals, Pfizer Inc., CV Therapeutics, Novartis), F.K. Welty (AstraZeneca); Honoraria: N.K. Wenger (Aventis, Pfizer Inc., Novartis, Merck & Co. Inc., Bristol-Myers Squibb, Eli Lilly Inc., DuPont Pharma, Searle), S.J. Lewis (Pfizer Inc., AstraZeneca, Merck & Co. Inc., Bristol-Myers Squibb), V. Bittner (Merck & Co. Inc., Merck Schering-Plough, Kos Pharmaceuticals, Pfizer Inc.), F.K. Welty (AstraZeneca, Pfizer Inc.); Grants received: N.K. Wenger (Eli Lilly Inc., AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., Wyeth Ayerst, Merck & Co. Inc.), S.J. Lewis (Pfizer Inc., AstraZeneca), D.M. Herrington (Pfizer Inc.), V. Bittner (Pfizer Inc., Merck & Co. Inc., National Institutes of Health, Kos Pharmaceuticals); Grants pending: V. Bittner (Merck & Co. Inc.); Receipt of payment for manuscript preparation: V. Bittner (Pfizer Inc; attended investigator meetings at which the manuscript was discussed); Other: N.K. Wenger (data safety monitoring boards of Procter & Gamble, Knoll Pharmaceuticals, Pfizer Inc.)
That’s alright then.
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